Supplementary Materials s3

A SYSTEMATIC REVIEW AND META-ANALYSIS OF EARLY GOAL-DIRECTED THERAPY FOR SEPTIC SHOCK: THE ARISE, ProCESS AND ProMISe INVESTIGATORS

SUPPLEMENTARY MATERIALS

TABLE OF CONTENTS PAGE

1. THE ARISE, PROCESS, PROMISE AND PRISM INVESTIGATORS 2

2. SEARCH STRATEGY 3

3. INCLUDED STUDIES 4

4. SUPPLEMENTARY FIGURES 5

Figure S1. Random-effects model for primary mortality outcome for patients presenting

to the emergency department with septic shock

Figure S2. In-hospital mortality

Figure S3. 28-day mortality

Figure S4. Receipt and duration of invasive mechanical ventilation

Figure S5. Receipt and duration of vasopressors

Figure S6. Receipt and duration of renal replacement therapy

Figure S7. Hospital length of stay

Figure S8. Effect of EGDT on primary mortality outcome for patients with septic shock

irrespective of presenting source

Figure S9. Funnel plot for primary mortality outcome of individual studies

5. SUPPLEMENTARY TABLES 17

Table S1. Receipt and duration of organ support

Table S2. ICU admission and length of stay in ICU and hospital

Table S3. Quality assessment for included studies

6. ACKNOWLEDGEMENTS 20

1. The ARISE, ProCESS, ProMISE and PRISM Investigators

ARISE Investigators: S.L. Peake, A. Delaney, M. Bailey, R. Bellomo, P.A. Cameron, D.J. Cooper, A.M. Higgins, A. Holdgate, B.D. Howe, S.A.R. Webb, P. Williams; ProCESS Investigators: D.M. Yealy, J.A. Kellum, D.T. Huang, P.C. Hou, A.E. Barnato, L.A. Weissfeld, F. Pike, T. Terndrup, H.E. Wang, F. LoVecchio, M Filbin, N.I. Shapiro, D.C. Angus; ProMISe Investigators: D. Bell, J.F. Bion, T.J. Coats, R.D. Grieve, D.A. Harrison, S.E. Harvey, R. Jahan, P.R. Mouncey, T.M. Osborn, G.S. Power, K.M. Rowan, M.Z. Sadique, M. Singer, J. Tan, J.D. Young; PRISM Investigators: M.C. Reade.

Clinical Trials Unit, Intensive Care National Audit & Research Centre, London (J.Tan); Burns, trauma and critical care research centre, University of Queensland, Brisbane, QLD and Joint Health Command, Australian Defence Force, Canberra, ACT (M.C.Reade).

All other investigator affiliations and a full list of site investigators for the ARISE, ProCESS and ProMISE trials are available in the original study reports:

ARISE Investigators, ANZICS Clinical Trials Group, Peake SL, Delaney A, Bailey M, Bellomo R, Cameron PA, Cooper DJ, Higgins AM, Holdgate A, Howe BD, Webb SA, Williams P (2014). Goal-directed resuscitation for patients with early septic shock. N Engl J Med 371:1496-506

ProCESS Investigators, Yealy DM, Kellum JA, Huang DT, Barnato AE, Weissfeld LA, Pike F, Terndrup T, Wang HE, Hou PC, LoVecchio F, Filbin MR, Shapiro NI, Angus DC (2014). A randomised trial of protocol-based care for early septic shock. N Engl J Med 370:1683-93

Mouncey PR, Osborn TM, Power, GS, Harrison DA, Sadique MZ, Grieve RG, Jahan R, Harvey SE, Bell D, Bion JF, Coats TJ, Singer M, Young JD, Rowan KM, ProMISe Trial Investigators (2015). Trial of early, goal-directed resuscitation for septic shock. N Engl J Med, doi:10.1056/NEJMoa1500896

2. SEARCH STRATEGY

Medline via PUBMED interface

(central venous oxygen saturation) OR (goal directed therapy) OR (goal directed resuscitation) OR (ScvO2) OR ScvO2) OR (clinical protocol) OR (sepsis protocol) OR (EGDT) OR (early goal directed therapy)

AND

(sepsis) OR (septicaemia) OR (septic shock))

AND

(clinical[Title/Abstract] AND trial[Title/Abstract]) OR clinical trials[MeSH Terms] OR clinical trial[Publication Type] OR random*[Title/Abstract] OR random allocation[MeSH Terms] OR therapeutic use[MeSH Subheading])

Searched from1/1/2000 until 15/1/2015

EMBASE and Cochrane Central Register of Clinical Trials via Ovid interface

1. exp *sepsis/

2. septicemia.mp.

3. exp Shock, septic/

4. 1 or 2 or 3

5. early goal directed therapy.mp.

6. EGDT.mp.

7. sepsis protocol.mp.

8. exp clinical protocols/

9. scvo2.mp.

10. goal directed resuscitation.mp.

11. goal directed therapy.mp.

12. 5 or 6 or 7 or 8 or 9 or 10 or 11

13. central venous oxygen saturation.mp.

14. 12 or 13

15. random:.tw.

16. clinical trial:.mp.

17. exp health care quality/

18. 15 or 16 or 17

19. 4 and 14 and 18

20. limit 19 to human

21. limit 20 to yr="2000-Current"

Searched from 1/1/2000 until 15/1/2015

3. INCLUDED STUDIES

Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M; Early Goal-Directed Therapy Collaborative Group (2001). Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 8;345:1368-77

Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA; Emergency Medicine Shock Research Network (EMShockNet) Investigators (2010). Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomised clinical trial. JAMA 303:739-46

de Oliveira DS, Gottschald AF, Moura JD, Costa GA, Ventura AC, Fernandes JC, Vaz FA, Carcillo JA, Rivers EP, Troster EJ (2008). ACCM/PALS haemodynamic support guidelines for paediatric septic shock: an outcomes comparison with and without monitoring central venous oxygen saturation. Intensive Care Med 34:1065-75

Wang X, Lu CJ, Gao FQ, Li XH, Yan WF, Ning FY (2006). Efficacy of goal-directed therapy in the treatment of septic shock. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 18:661-4

Early Goal-Directed Therapy Collaborative Group of Zhejiang Province (2010). The effect of early goal-directed therapy on treatment of critical patients with severe sepsis/septic shock: a multi-centre, prospective, randomised, controlled study. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 22:331-4

Tian HH, Han SS, Lv CJ, Wang T, Li Z, Hao D, Shang QM, Wang XZ (2012). The effect of early goal lactate clearance rate on the outcome of septic shock patients with severe pneumonia. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 24:42-5

Yu B, Tian HY, Hu ZJ, Zhao C, Liu LX, Zhang Y, Zhu GJ, Wang LT, Wu XH, Li J (2013). Comparison of the effect of fluid resuscitation as guided either by lactate clearance rate or by central venous oxygen saturation in patients with sepsis. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 25:578-83

Lu N, Zheng R, Lin H, Shao J, Yu J (2014). Clinical studies of surviving sepsis bundles according to PiCCO on septic shock patients. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue 26:23-7

4. SUPPLEMENTARY FIGURES

Figure S1. Random-effects model of primary mortality outcome for patients presenting to the emergency department with septic shock

EGDT denotes early goal-directed therapy; OR, odds ratio; CI, confidence interval. The control was usual care or another non-EGDT resuscitation strategy.

Random-effects model. The individual points denote the OR of each study and the lines either side the 95% confidence intervals. The vertical line denotes the null effect. The control for the ProCESS trial includes both usual care and protocol-based standard therapy groups combined.

Figure S2. In-hospital mortality for patients presenting to the emergency department with septic shock

A. Fixed-effect model

B. Random-effects model

EGDT denotes early goal-directed therapy; OR, odds ratio; CI, confidence interval. The control was usual care or another non-EGDT resuscitation strategy. The individual points denote the OR of each study and the lines either side the 95% confidence intervals. The vertical lines denote the null effect. The control for the ProCESS trial includes both usual care and protocol-based standard therapy groups combined.

Figure S3. 28-day mortality for patients presenting to the emergency department with septic shock

A. Fixed-effect model

B. Random-effects model

Figure S4. Receipt and duration of invasive mechanical ventilation for patients presenting to the emergency department with septic shock

A. Receipt of invasive mechanical ventilation (fixed-effect model)

B. Receipt of invasive mechanical ventilation (random-effects model)

C. Duration of invasive mechanical ventilation (days) (fixed-effect model)

EGDT denotes early goal-directed therapy; OR, odds ratio; CI, confidence interval; WMD, weighted mean difference; SD, standard deviation. The control was usual care or another non-EGDT resuscitation strategy.

The individual points denote the OR or WMD of each study and the lines either side the 95% confidence intervals. The vertical lines denote the null effect. The control for the ProCESS trial includes both usual care and protocol-based standard therapy groups combined.

Figure S5. Receipt and duration of vasopressors for patients presenting to the emergency department with septic shock

A. Receipt of vasopressors (fixed-effect model)

B. Receipt of vasopressors (random-effects model)

C. Duration of vasopressors (days) (fixed-effect model)

Figure S6. Receipt and duration of renal replacement therapy for patients presenting to the emergency department with septic shock

A. Receipt of renal replacement therapy

B. Duration of renal replacement therapy (days)

Fixed-effect model. The individual points denote the OR or WMD of each study and the lines either side the 95% confidence intervals. The vertical line denotes the null effect. The control for the ProCESS trial includes both usual care and protocol-based standard therapy groups combined.

Figure S7. Hospital length of stay for patients presenting to the emergency department with septic shock (days)

EGDT denotes early goal-directed therapy; WMD, weighted mean difference; CI, confidence interval; SD, standard deviation. The control was usual care or another non-EGDT resuscitation strategy

Fixed-effect model. The individual points denote the WMD of each study and the lines either side the 95% confidence intervals. The vertical line denotes the null effect. The control for the ProCESS trial includes both usual care and protocol-based standard therapy groups combined.

Figure S8. Effect of EGDT on primary mortality outcome for patients with septic shock irrespective of presenting source

A. Fixed-effect model by sub-group according to presenting source

B. Random-effects model by sub-group according to presenting source

Post-hoc analysis of the interaction between presenting source (emergency department versus general ward/ intensive care unit or source unknown) and the effect of EGDT did not find any sub-group interaction (P=0.51)

Figure S9. Funnel plot for primary mortality outcome of individual studies

The dots represent those studies conducted in patients presenting to the emergency department with septic shock (primary objective) and the triangles those studies in which some or all the patients enrolled were from the general ward and /or intensive care unit or the source was unable to be determined from either the published article or from direct communication with the author (secondary objective).

5. SUPPLEMENTARY TABLES

Table S1. Receipt and duration of organ support

Author / Invasive ventilation, % / Duration of
ventilation, days / Vasopressor support, % / Duration of vasopressors, days / RRT, % / Duration of
RRT, days
EGDT / Control / EGDT / Control / EGDT / Control / EGDT / Control / EGDT / Control / EGDT / Control
Primary objective
Rivers et al. / 55.4 / 70.7 / 9.0 ± 11.4 / 9.0 ± 13.1 / 36.1 / 51.1 / 1.9 ± 3.1 / 2.4 ± 4.2 / NA / NA / NA / NA
Jones et al. / 46.0 / 50.0 / NAa / NAa / 72.0 / 66.7 / NA / NA / NA / NA / NA / NA
ProCESS Investigators / 38.0 / 34.4 / 6.4 ± 8.4 / 8.4 ± 7.3 / 61.3 / 59.9 / 2.6 ± 1.6 / 2.5 ±1.6 / 3.1 / 4.4 / 7.1 ± 10.8 / 8.6 ± 12.4
ARISE Investigators / 30.1 / 31.5 / 6.2 ± 9.0 / 4.7 ± 5.4 / 76.6 / 65.8 / 2.6 ± 4.9 / 2.5 ± 3.4 / 13.4 / 13.6 / 8.5 ± 17.1 / 9.0 ± 16.9
ProMISe Investigators / 28.9 / 28.5 / 6.6 ± 7.1 / 6.2 ± 6.7 / 60.5 / 55.0 / NA / NA / 14.2 / 13.2 / 4.8 ± 5.5 / 5.1 ± 4.3
Secondary objective
Wang et al. / 68.8 / 76.5 / NA / NA / 100 / 100 / NA / NA / 18.8 / 29.4 / NA / NA
De Oliviera et al. / 70.6 / 80.4 / NAb / NAb / 72.6 / 74.5 / NAb / NAb / NA / NA / NA / NA
EGDT collaborative / NA / NA / 13.2 ± 1.5 / 14.4 ± 1.6 / NA / NA / NA / NA / NA / NA / NA / NA
Tian et al. / NA / NA / 6.4 ± 4.0 / 5.7 ± 4.2c / NA / NA / NA / NA / NA / NA / NA / NA
Yu et al. / 76.0 / 80 / NA / NA / 64.0 / 64 / NA / NA / NA / NA / NA / NA
Lu et al. / 100 / 100 / 6.0 ± 1.2 / 4.1± 0.9 / 100 / 100 / NA / NA / NA / NA / NA / NA

Data presented as mean ± SD or proportions (%) unless otherwise indicated. ProCESS denotes Protocolized Care for Early Septic Shock; ARISE, Australasian Resuscitation in Sepsis Evaluation; ProMISe, Protocolised Management in Sepsis; EGDT, early goal-directed therapy; NA, not available; RRT, renal replacement therapy. The primary objective included only those studies in which patients presented to the emergency department with septic shock. The secondary objective included those studies in which the presenting source was the emergency department and the ward or intensive care unit or where the source was not known. The control for all analyses was usual care or another non-EGDT resuscitation strategy. For ProCESS, data presented for the control group is usual care and protocol-based standard therapy groups combined.